EP2319804B1 - Adsorbant de phosphate à base d'iron(III)-glucides - Google Patents

Adsorbant de phosphate à base d'iron(III)-glucides Download PDF

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Publication number
EP2319804B1
EP2319804B1 EP11152584.6A EP11152584A EP2319804B1 EP 2319804 B1 EP2319804 B1 EP 2319804B1 EP 11152584 A EP11152584 A EP 11152584A EP 2319804 B1 EP2319804 B1 EP 2319804B1
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EP
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Prior art keywords
iron
iii
phosphate
phosphate adsorbent
adsorbent
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EP11152584.6A
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German (de)
English (en)
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EP2319804A1 (fr
Inventor
Michael Ambühl
Corine Gessier-Vial
Christa Hartmann
Daniel Kaufmann
Ernst Küsters
Ulrich Meier
Andreas Meyer
Nabila Sekkat
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Elanco Tiergesundheit AG
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Novartis AG
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Priority claimed from EP06126122A external-priority patent/EP1932807A1/fr
Application filed by Novartis AG filed Critical Novartis AG
Priority to SI200731582T priority Critical patent/SI2319804T1/sl
Priority to EP11152584.6A priority patent/EP2319804B1/fr
Priority to PL11152584T priority patent/PL2319804T3/pl
Publication of EP2319804A1 publication Critical patent/EP2319804A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/02—Iron compounds
    • C07F15/025—Iron compounds without a metal-carbon linkage
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/0203—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of metals not provided for in B01J20/04
    • B01J20/0225—Compounds of Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt
    • B01J20/0229—Compounds of Fe
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/06—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising oxides or hydroxides of metals not provided for in group B01J20/04
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/24—Naturally occurring macromolecular compounds, e.g. humic acids or their derivatives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/2803—Sorbents comprising a binder, e.g. for forming aggregated, agglomerated or granulated products
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G49/00—Compounds of iron
    • C01G49/0018—Mixed oxides or hydroxides
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G49/00—Compounds of iron
    • C01G49/02—Oxides; Hydroxides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2220/00—Aspects relating to sorbent materials
    • B01J2220/40—Aspects relating to the composition of sorbent or filter aid materials
    • B01J2220/46—Materials comprising a mixture of inorganic and organic materials

Definitions

  • the present invention relates to new iron containing phosphate adsorbent, process for its production, uses thereof and pharmaceutical compositions containing it.
  • Phosphorus is critical for bone mineralization, cellular structure, genetic coding, and energy metabolism. Many organic and inorganic forms exist. Phosphorus is present in nearly all foods, and Gl absorption of dietary forms is very efficient. Phosphorus homeostasis normally is maintained through several mechanisms (renal excretion, cellular release, hormonal control, etc). When the phosphorus load (from Gl absorption, exogenous administration, or cellular release) exceeds renal excretion and tissue uptake, hyperphosphatemia occurs.
  • Hyperphosphatemia is associated with significant increase in morbidity and mortality, and may induce severe complications, such as hypocalcemia, decreasing of vitamin D production, metastatic calcification. Hyperphosphatemia is also contributing to the increased incidence of cardiovascular disease among dialysis-dependent patients, and can result in bone pathology.
  • At least 70% of patients with renal insufficiency or renal failure show hyperphosphatemia.
  • restricting intake of dietary phosphorus is not sufficient to reduce serum phosphate levels into the normal range, and oral phosphate binders need to be taken.
  • Calcium and aluminium salts orally taken as treatment for hyperphosphatemia are known. But there are concerns regarding their long-term safety.
  • the traditional aluminium-based phosphate binders have the drawback of side effects due to aluminium absorption (osteomalacia, encephalopathy, microcytic anaemia).
  • Calcium-containing phosphate binders (calcium carbonate or calcium acetate) may aggravate metastatic calcification, particularly if they are taken together with vitamin D analogues and a high calcium dialysate concentration.
  • ZerenexTM An iron-based ferric citrate phosphate binder, known as ZerenexTM, is described in US 6,903,235B .
  • ZerenexTM is an oral, inorganic, iron-based compound that has the capacity to bind phosphorous and form non-adsorbable complexes. Since this product is soluble its long term administration may induce an increase of the concentration of iron in gastrointestinal tract, which may be safety issue as mentioned hereinabove.
  • Sevelamer a synthetic polymer commercialized by Genzyme under the name of Renagel ® , poly(allylamine-co-N,N'-diallyl-1,3-diamino-2-hydroxypropane) hydrochloride is an iron exchange gel matrix.
  • WO9201458 discloses a method of controlling serum phosphate level in patients by iron oxy-hydroxides which bind to ingested phosphate.
  • US 6,174,442 or DE 102004031181 A1 describe an adsorbent for phosphate which contains polynuclear ⁇ -iron hydroxide stabilized by carbohydrates and/or humic acid.
  • WO 2006/000547 describes an adsorbent for phosphate which is obtained from iron(III) nitrate or sulfate and is stabilized by starch and sucrose.
  • the phosphate binding capacity of the known phosphate adsorbents containing oxide hydroxides is limited. Furthermore, the processes described to manufacture such compounds are not suitable for preparing larger amounts of compounds.
  • the possible release of iron under physiological conditions from any iron containing drugs or compounds, in particular in case of the phosphate adsorbent described in US 6,174,442 may be a safety issue, since excess iron is toxic to body organs.
  • the daily release of iron should not be higher than 20mg iron per day.
  • a too high release of iron can particularly problematic in case of patients suffering from haemochromatosis.
  • Haemochromatosis is a very common genetic disorder of iron metabolism wherein absorption of iron through the intestine is uncontrolled even when body saturation levels have been reached.
  • the available phosphate binders and the phosphate adsorbents described in the prior art bind not more than about 120mg phosphate per gram of product.
  • the amount of adsorbent e.g. the amount and/or number of oral dosage forms containing it to be taken every day must be high.
  • the average daily dosage to be taken by dialysis patients in order to avoid/treat hyperphosphatemia is of about 9 capsules in case of ZerenexTM, and of 14 film coated tablets in case of Renagel ® . This indicates that the patient compliance of the available phosphate adsorbents is very low.
  • the present invention provides a new phosphate adsorbent containing iron(III) oxide-hydroxide having higher phosphate binding capacity than the phosphate adsorbent available yet, or than the iron(III)-based phosphate adsorbent described in the prior art, as well as uses thereof and pharmaceutical compositions containing it.
  • the present invention pertains to a polynuclear iron(III)-based phosphate adsorbent comprising i) an adsorbent base material, preferably a non soluble carbohydrate, ii) polynuclear iron(III) oxide hydroxides, and iii) a soluble carbohydrate, wherein the soluble carbohydrate is incorporated, e.g.
  • the polynuclear iron oxide hydroxides may be stabilized by soluble carbohydrates.
  • the iron(III)-based phosphate adsorbent may further comprise a carbonate; the carbonate may partially incorporated, e.g. partially incorporated, into the polynuclear iron(III) oxide hydroxides.
  • the present invention further provides an iron(III)-based phosphate adsorbent containing polynuclear iron(III) oxide hydroxides wherein the polynuclear iron oxide hydroxide contains polynuclear gamma-iron oxide hydroxides, and optionally ferrihydrite, e.g. traces of ferrihydrite.
  • the polynuclear iron oxide hydroxide may be stabilized by soluble carbohydrates.
  • the iron(III)-based phosphate adsorbent according to the present invention is a complex formed with polynuclear iron(III) oxide hydroxides, insoluble carbohydrate such as starch, and soluble carbohydrate such glucose derivative (e.g. sucrose or maltodextrin).
  • the iron oxide-hydroxide contained in the iron(III)-based phosphate adsorbent according to the present invention would then be a complex, as a whole insoluble under the physiological conditions, which is stabilized by the glucose derivative.
  • the glucose derivative is probably acting by preventing the phosphate adsorbent from being overdried during its purification, as overdrying would lead to a loss of the phosphate binding capacity.
  • the present invention further provides a manufacture process for producing an iron(III) based phosphate adsorbent.
  • a manufacture process for producing an iron(III) based phosphate adsorbent In particular there is provided a process for manufacturing and isolating the iron(III) based phosphate adsorbent in a form which is easily packaged, e.g. as a dry powder suitable for direct sachet filling.
  • the present invention provides a manufacture process for preparing oxide-hydroxide of iron having gamma-configuration from iron (III), i.e. a manufacture process for preparing oxide-hydroxide of iron(III) having gamma-configuration.
  • Iron(III)-based phosphate adsorbent Iron(III)-based phosphate adsorbent.
  • iron oxide-hydroxide containing compound having a good phosphate binding capacity which can be used as a pharmaceutical
  • iron oxide-based compound which is stable.
  • iron oxide-hydroxides in particular iron(III) oxide-hydroxides
  • iron(III) oxide-hydroxides are not stable compounds: during time ageing occurs which leads to the re-grouping of initially randomly placed molecules and to the formation of a more or less regular crystal lattice. Ageing usually not only involves crystallization but also particle enlargement. Such ageing may alter the phosphate binding of an iron oxide-hydroxide based phosphate adsorbent. Such an ageing may also lead to an iron-based phosphate adsorbent which does release iron.
  • iron(III)-based phosphate adsorbent which does not release iron, or does release only small amounts of iron under physiological conditions, e.g. an iron amount smaller than the daily acceptable dosage of 20mg iron. This means that there is a need to provide an iron(III)-based phosphate adsorbent which has a low bioavailability, preferably which is not bioavalaible at all.
  • phosphate adsorbent of the invention for the adsorption of phosphate, which has higher phosphate binding capacity than the phosphate adsorbents of the prior art, as herein defined as "phosphate adsorbent of the invention” or "compound of the invention".
  • Higher phosphate binding capacity means about 15% higher than the phosphate adsorbents known in the art, e.g. at least 20% higher, e.g. at least 25% higher, e.g. at least 30% higher e.g. than the adsorbent described in US 6,174,442 .
  • the compound of the invention may adsorb more than about 12%m/m phosphate, preferably more than about 14%m/m, even more preferably about or more than about 20% m/m.
  • .%m/m refers to percentage of mass to mass, i.e. to the amount of phosphate (calculated as PO 4 3- ) being adsorbed (in g) by 1 g of phosphate adsorbent.
  • an iron-based phosphate adsorbent comprising i) an adsorbent base material, preferably a non soluble carbohydrate, ii) polynuclear iron (III) oxide hydroxides, and iii) a soluble carbohydrate, wherein the soluble carbohydrate is partially incorporated into the polynuclear iron(III) oxide hydroxides.
  • partially incorporated means that about 10 to 20 % by weight of the soluble carbohydrate, based on the total weight of the phosphate adsober, are incorporated into the polynuclear iron (III) oxide hydroxides, i.e. can not be removed by washing the phosphate adsober.
  • adsorbent base material refers to a porous material, preferably having organic or inorganic OH groups, e.g. non soluble carbohydrates; organic polymer or copolymer; natural semisynthetic or synthetic linear and/or branch-chained; soluble or insoluble polyhydroxyl compounds (e.g. polyvinyl alcohol); inorganic supports, e.g. based on silicon dioxide and/or silicates such as glyceryl-modified glasses.
  • Preferred adsorbent base materials are non soluble carbohydrates.
  • non soluble carbohydrates examples include starch, agarose, dextran, dextrin, cellulose.
  • Preferred non soluble carbohydrate is starch.
  • soluble carbohydrate refers to glucose derivatives, such as sucrose, maltodextrin or mixture thereof.
  • Preferred soluble carbohydrate is sucrose.
  • the iron-based phosphate adsorbent of the invention is a iron(III) oxide-hydroxide containing compound, comprising a soluble carbohydrate such as a glucose derivative (e.g. sucrose or maltodextrin), and starch.
  • a soluble carbohydrate such as a glucose derivative (e.g. sucrose or maltodextrin), and starch.
  • the phosphate adsorbent may be defined as a complex formed with polynuclear iron(III) oxide hydroxides, starch and the glucose derivative (e.g. sucrose or maltodextrin, preferably sucrose).
  • the polynuclear iron oxide hydroxides is bound to the adsorbent base material, e.g. starch.
  • the compound of the invention comprises starch particles covered by iron(III) oxide-hydroxide and optionally stabilized by a glucose derivative such as sucrose, maltodextrin or mixture thereof.
  • a glucose derivative such as sucrose, maltodextrin or mixture thereof.
  • the iron is homogenously distributed on the surface of the particles.
  • a new iron-based phosphate adsorbent which releases little iron in simulated gastric fluids (as defined in Pharmacopeia).
  • the phosphate adsorbent of the invention does not significantly release iron at a pH range above 2 up to 10.
  • 10 g of the phosphate adsorbent of the invention may release less than about 20mg of iron at pH's above 2.
  • the compound of the invention may contain about 10 to about 35wt%, e.g. about 20 to about 30 wt%, preferably at least about 20 weight % of non soluble carbohydrate, e.g. starch, for example about 10 to 30, e.g. about 30, e.g. about 28 weight % of starch, based on the total weight of the compound.
  • a new phosphate adsorbent containing iron (III) oxide-hydroxide and starch which contains about 5 to about 50 weight % of soluble carbohydrate, e.g. about 10 to about 40 weight % , e.g. about 12 to about 30 weight %, based on the total weight of the adsorbent.
  • the adsober of the invention contains at least about 10 weight % of sucrose, maltodextrin or mixture thereof (preferably sucrose), for example at least about 14 weight % of sucrose, maltodextrin or mixture thereof (preferably sucrose), for example about 28 wt% of sucrose, maltodextrin or mixture thereof (preferably sucrose), based on the total weight of the compound.
  • a new phosphate adsorbent containing iron(III) oxide-hydroxide which contains more than about 5 weight% of water, for example about 5 to about 10 weight%, for example about 5 to about 8 weight %, based on the total weight of the compound.
  • the phosphate adsorbent of the invention contains at least about 10 weight% of iron, for example at least about 18 weight %, for example about 30 weight% of iron, e.g. iron(III), based on the total weight of the adsorbent.
  • the iron content of the compound of the invention is about 10 to about 35 weight %, for example about 15 to about 30 weight %, for example about 25 to about 30 weight %, based on the total weight of the compound.
  • a new iron(III)-based phosphate adsorbent comprising starch and a glucose derivative such as sucrose, maltodextrin or mixture thereof (preferably sucrose), which contains about 5 to about 10 weight% of water, about 20 to about 30 weight% of iron, based on the total weight of the adsorbent.
  • the phosphate adsorbent of the invention comprises iron(III), more preferably ⁇ -iron(III) oxide-hydroxide, optionally mixed to ferrihydrite.
  • the polynuclear iron oxide hydroxide of the phosphate adsorbent consists of gamma-iron oxide hydroxide (preferably gamma-iron(III) oxide hydroxide) or mixture of gamma-iron oxide hydroxide with ferrihydrite.
  • the compound of the invention is x-ray amorphous.
  • the phosphate adsorbent of the invention is obtained by reacting an aqueous solution of an iron salt, preferably an iron(III) salt, with an aqueous base wherein the precipitation of the salt is performed in presence of an insoluble carbohydrate, preferably starch.
  • the resulting iron oxide hydroxide is stabilized by adding a soluble carbohydrate to the precipitate before the iron hydroxide ages.
  • the present invention also includes a new process for the preparation of gamma-iron(III) oxide-hydroxide, which process comprises the steps of reacting an aqueous solution of an iron (III) salt with an aqueous base, at pH comprised between 6 and 10, optionally in presence of starch. Starch may be added after the reaction of step a), i.e. after the after the complete mixing of the iron salt with the base.
  • starch may be added in a further step (step b), e.g. after the complete mixing of the iron salt with the base.
  • starch is added in step a) and more starch is added in step b).
  • the precipitation of the salt by the base is done in presence of starch.
  • the obtained precipitate is isolated and washed, as hereinbelow defined.
  • the aqueous base may consist of an aqueous basic mixture of a base and starch.
  • the reaction may be performed at ambient temperature, or preferably at low temperature.
  • the iron salt may be iron(III) chloride, iron(III) nitrate or iron(III) sulfate, preferably the iron salt is iron chloride.
  • the iron(III) oxide-hydroxide obtained by that process has gamma configuration. Small amounts of ferrihydrite, e.g. traces thereof, may also be present.
  • Iron(III)-based phosphate adsorbent manufacture process Iron(III)-based phosphate adsorbent manufacture process.
  • iron oxide-hydroxide containing phosphate adsorbent in an excellent quality, i.e. homogenous and stable, by having carbohydrates, e.g. starch and/or sucrose, present during the reaction of the iron with the base and/or by carefully controlling the pH of that reaction.
  • carbohydrates e.g. starch and/or sucrose
  • the presence of the carbohydrates prevent the ageing of the iron oxide-hydroxide, i.e. the conversion of the initially formed iron oxide-hydroxide to a less potent phosphate binder.
  • a product with an unexpected high phosphate binding capacity can be synthesized.
  • the present invention also includes a process for the preparation of a iron(III)-based phosphate adsorbent comprising iron(III) oxide-hydroxide, insoluble carbohydrate (e.g. starch) and a soluble carbohydrate (e.g. glucose derivative), which process comprises the steps of
  • step i) the aqueous solution of iron(III) salt with the aqueous base leads first to nucleation and then to precipitation of the iron oxide hydroxide.
  • the nucleation may be performed in presence of the insoluble carbohydrate, e.g. starch, or the carbohydrate may be added after the nucleation, and before the precipitation.
  • the precipitation of the salt is performed in presence of the insoluble carbohydrate, preferably starch.
  • the insoluble carbohydrate may be added before the precipitation occurs, or during the precipitation.
  • the insoluble carbohydrate is added before the precipitation is complete.
  • the aqueous solution of iron(III) salt is mixed to the aqueous base in presence of the insoluble carbohydrate, e.g. starch.
  • the insoluble carbohydrate e.g. starch.
  • additional insoluble carbohydrate is then added.
  • the insoluble carbohydrate is added only after having mixed the aqueous base with the iron salt, for example after the precipitation of the iron salt has started.
  • the insoluble carbohydrate may stabilize the precipitate.
  • performing the precipitation in presence of an insoluble carbohydrate increases the phosphate binding capacity of the iron(III)-based compound thus obtained, preferably starch.
  • the resulting iron oxide hydroxide may be stabilized by adding a soluble carbohydrate to the precipitate before the iron hydroxide ages.
  • the iron(III) salt may be iron(III) chloride, iron(III) nitrate or iron(III) sulfate, preferably the iron salt is iron(III) chloride, e.g. solid iron(III)chloride hexahydrate.
  • the aqueous solution of iron(III) salt may be in particular a solution of iron(III) salt, as herein above defined, in water.
  • the solution of iron salt may comprise from about 3 to about 35 wt/wt%, e.g. 20 to about 30 wt/wt% of iron salt, preferably about 25 wt/wt% of iron salt, based on the total weight of the iron salt.
  • iron alum e.g. KFe(SO 4 ) 2 or NH4Fe(SO 4 ) 2
  • sulfuric-acid-containing solutions e.g. of iron (III) sulfate.
  • the base to be used may be hydroxide or carbonates of alkali or alkaline earth metals. Alkali carbonates, alkali bicarbonates and alkali metal hydroxides (e.g. of sodium) are preferred.
  • the base may be selected from LiOH, KOH, NaOH, Ca(OH) 2 , Mg(OH) 2 , Li 2 CO 3 , K 2 CO 3 , CaCO 3 , MgCO 3 , preferably Na 2 CO 3 .
  • the base solution may comprise about 20 to about 30, e.g. about 22 to about 27, e.g. about 25.5 vol% of base, based on the total volume of the solution.
  • the aqueous base may consist of an aqueous solution containing a base, as hereinabove defined, and an insoluble carbohydrate, e.g. starch.
  • the amount of base is chosen in order to obtain the desired pH, e.g. to adjust the pH of the solution resulting from the mixture with the aqueous solution of iron(III) salt to a pH between about 6 and 10, preferably about 6 and 8, more preferably about 6.5 and 7.5, even more preferably around 7.
  • Starch may be selected from corn, wheat, rice, maize or potato starch, and mixture thereof. Starch may also contain part of soluble starch (e.g. maltodextrin). For example, starch may be a mixture of 80 wt% or more of potato starch and 20wt % or less of soluble starch, e.g. 80 wt% or more of potato starch and 20wt % or less of maltodextrin. In another embodiment of the invention, the starch is replaced by a dietary fiber, e.g. Benefiber ® (produced by Novartis AG). Preferably starch is potato starch.
  • a dietary fiber e.g. Benefiber ® (produced by Novartis AG).
  • Benefiber ® produced by Novartis AG
  • insoluble carbohydrate e.g. starch
  • iron salt e.g. per about 1.0 to about 20 g of iron salt, e.g. per about 1.5 to about 10 g of iron salt, e.g. per about 2.0 to about 15 g of iron salt.
  • step i) the pH of the solution is maintained constant at a pH between 6 and 8, preferably around 7, during all the mixing.
  • the pH can be adjusted to the desired value.
  • the reaction in particular step i), is preferably made at a temperature between about 1 and 20, preferably 2 to 10, preferably about 5°C.
  • step i) is performed at ambient temperature.
  • the suspension may stagnate for a short time, e.g. more than 1 hour, preferably during 1 to 5 hours, more preferably over night. During that time, the suspension can be stirred.
  • the soluble carbohydrate may be a glucose derivative.
  • Glucose derivatives may be selected from agarose, dextran, dextrin, dextran derivatives, cellulose, cellulose derivatives, sucrose, maltose, lactose, mannitol and mixture thereof.
  • Preferred glucose derivatives are sucrose, maltodextrin and mixture thereof. Most preferred glucose derivative is sucrose.
  • the amount of soluble carbohydrate, e.g. glucose derivative, added in step iv) may be of about 5 to about 15%wt, preferably about 5 to about 10, based on the weight of the phosphate adsorbent. Preferably about 5 to about 15 weight% sucrose or about 5 to about 10 weight% sucrose is used.
  • the precipitate obtained in step i) may be washed, at least one time.
  • step ii) the obtained precipitate is isolated, e.g. by decantation, filtration, centrifugation, preferably by decantation, and then washed.
  • the washing is performed with water or an aqueous solution of NaHCO 3 preferably with water. Combinations of water washings and NaHCO 3 -washings may be used.
  • the precipitate is washed once or several times, preferably several times. Washing can be done until the level of impurities is down to a predefined level, e.g. from a few hours up to a few days. Preferably 2 to 5 washings are done, more preferably 3 to 5.
  • the water or washing solution is removed by decantation, filtration, centrifugation, preferably by decantation.
  • the product is not completely dried.
  • the product is then resuspended in water.
  • a minimum amount of water is needed so that the suspension can be processable.
  • the ratio amount of water/final phosphate adsorbent may be from about 0.8 to about 2, preferably 1.1. to 1.5, more preferably about 1.
  • the resulting aqueous suspension of phosphate adsorbent has approximately a neutral pH value in the range of about 6 .5 to 7.5.
  • the suspension may also be done in presence of a soluble carbohydrate as herein above defined, e.g. sucrose, e.g. the suspension is performed with an aqueous solution of soluble carbohydrate. Or the soluble carbohydrate.is added in a further step, after the precipitate is resuspended.
  • a soluble carbohydrate as herein above defined, e.g. sucrose, e.g. the suspension is performed with an aqueous solution of soluble carbohydrate.
  • the soluble carbohydrate. is added in a further step, after the precipitate is resuspended.
  • step iv) preferred soluble carbohydrate is sucrose.
  • the preservative may be a soluble preservative, such as e.g. chlorhexidien or p-hydroxy-benzoic acid ester, or an alcohol, such as e.g. ethanol, methanol, 2-propanol or combination thereof.
  • the preservative is an alcohol.
  • Preferred alcohol is ethanol.
  • the phosphate adsorbent resulting from step v) is not dried, e.g. not completely dried.
  • step vi a further step which consists of isolating the phosphate adsorbent.
  • Such an isolation may be made by filtration, decantation, spray drying or fluidized spray drying.
  • spray drying or fluidized spray drying e.g. fluidized bed spray drying is performed.
  • spray drying or fluidized spray drying e.g. fluidized bed spray drying is performed.
  • a process for manufacturing an iron(III)-based adsorbent having high phosphate binding capacity in form of a dry powder as hereinabove described, wherein the process further comprises a step of isolating the product by spray drying or fluidized spray drying.
  • fluidized bed spray drying is suitable to directly and continuously produce a well granulated, free flowing and dust free powder which is suitable for direct sachet filling or can be easily granulated to yield a granulate.
  • the surface area of the iron(III)-based phosphate adsorbent is increased, e.g. by adding a porous excipient, e.g. silicon dioxides, for example Aerosil, during the manufacture of the phosphate adsorbent, e.g. during step vi) as herein above described.
  • a porous excipient e.g. silicon dioxides, for example Aerosil
  • a formulation step may be performed. For example a step of mixing, granulating, encapsulating and/or tableting the phosphate adsorbent may be done, with adequate excipients if necessary.
  • the process further comprises the step vii) of granulating the powder, optionally in presence of at least one excipient selected from a binder and a lubricant, to yield an iron(III)-based phosphate adsorbent as a granulate
  • the process further comprises the step viii) of tabletting the product, i.e. tabletting either the powder obtained in step vi) or the granulate obtained in step vii).
  • the tabletting step is optionally performed in presence of an excipient selected from a filler, a binder, a disintegrant, a flow agent, a lubricant, and mixture thereof.
  • iron oxides are difficult to be manufactured because of their dustiness. Such a dustiness may also be problematic for formulating iron oxides containing compounds in form of pharmaceutical compositions and/or for packaging such compounds.
  • fine dust can be whirled by air or can even be inhalated, which may lead to losing part of the iron oxides, or taking an incorrect dosage thereof. Therefore it is important to prepare a pharmaceutical composition containing an iron(III)-based phosphate adsorbent which can be safety administered to the patients, in particular whose dosage can be controlled when taken by the patients.
  • the phosphate adsorbent In order to obtain an iron oxides containing phosphate adsorbent efficiently suitable as pharmaceutical which can be orally administered, it is necessary to obtain a compound which can be formulated into oral pharmaceutical compositions.
  • Typical oral formulation contain excipients present to facilitate automatic compaction or sachet filling. However addition of such excipients may affect the phosphate binding capacity of the adsorbent. Therefore in a preferred embodiment of the invention, the phosphate adsorbent is in form of a powder. Surprisingly it has now been found that by using dedicated processing conditions during the manufacture process, addition of such excipients may be avoided.
  • phosphate adsorbents Due to the daily amount of phosphate eaten every day through food intake and the relative low binding phosphate capacity of the phosphate adsorbents, patients who need to take such compounds, e.g. suffering from hyperphosphateamia, need to take high amount of them every day. Therefore there is a need to provide a phosphate adsorbents in a formulation which could improve patience compliance, for example in case of elderly or pediatric patients.
  • a formulation in form of a powder could improve patience compliance in comparison to the phosphate adsorbents commercially available, since the powder could be diluted in water and then permit to take higher doses of phosphate adsorbent with a low amount of liquid.
  • the inventors of the present invention were able to prepare an iron oxides containing phosphate adsorbent in form of a non-dusty and free-flowing powder without the use of excipients while maintaining the high phosphate binding capacity of the compound.
  • That powder can easily be manipulated, e.g. during processing or packaging.
  • that powder can be easily filled, e.g. mechanically filled, into sachets or stick packs.
  • the present invention provides a phosphate adsorbent which is free-flowing, almost dust-free and then can be filled into sachets or stick packs, e.g. automatically filled.
  • composition of the invention refers to pharmaceutical composition containing iron (III)-based phosphate adsorbent, e.g. the containing the phosphate adsorbent of the invention.
  • compositions according to the invention may be formulated in any conventional form, preferably oral dosage forms, e.g. powders, granules, granulates, capsules, sachets, stick packs, bottles (optionally together with adequate dosing systems, e.g., calibrated spoons), tablets, dispersible tablets, film coated tablets, or uniquely coated tablets
  • oral dosage forms e.g. powders, granules, granulates, capsules, sachets, stick packs, bottles (optionally together with adequate dosing systems, e.g., calibrated spoons), tablets, dispersible tablets, film coated tablets, or uniquely coated tablets
  • compositions according to the invention may also be formulated as semi-solid formulations, e.g. aqueous and non aqueous gel, swallowable gel, chewy bar, fast-dispersing dosage, cream ball chewable dosage form, chewable dosage forms, or edible sachet as defined hereinbelow.
  • semi-solid formulations e.g. aqueous and non aqueous gel, swallowable gel, chewy bar, fast-dispersing dosage, cream ball chewable dosage form, chewable dosage forms, or edible sachet as defined hereinbelow.
  • Preferred formulations are powder, granulate, tablet, for example dispersible tablet.
  • the pharmaceutical composition is prepared in the form of a powder or a granulated product (i.e. granulated powder or ganulates), which is optionally filled into powder containers such as bottle, capsule, sachet or stick pack.
  • powder containers such as bottle, capsule, sachet or stick pack.
  • a sachet or stick pack is supplied with a child resistant easy opening feature.
  • a lubricant as defned hereinbelow, may be added, for example in case the phosphate adsorbent of the invention, e.g. as prepared according to the manufacture process defined hereinabove, is filled into a capsule.
  • the granulated product may be prepared by dry granulation, e.g. roller compaction, or wet granulation, for example in a fluid bed or high shear mixer.
  • the granulation may be done in presence of a binder, e.g. MCC, in order to improve the mechanical stability of the granulate.
  • the granulates may be filled then into e.g. bottles, capsules, sachets or stick packs. In one embodiment of the invention such filling can be performed by automatically working systems.
  • the sachet or stick packs may contain between about 0.5 to 10g, e.g. from about 0,5 to 5 g of granulated product.
  • the pharmaceutical composition of the invention may contain a binder, e.g. dry binder, such as sucrose or microcrystalline cellulose (MCC).
  • a binder e.g. dry binder, such as sucrose or microcrystalline cellulose (MCC).
  • the pharmaceutical composition of the invention may contain a lubricant, e.g. Mg-stearate or hydrophilic lubricant, such as PEG 6000 or PEG 4000.
  • a lubricant e.g. Mg-stearate or hydrophilic lubricant, such as PEG 6000 or PEG 4000.
  • the invention provides a capsule containing the iron(III)-based phosphate adsorbent, e.g. as a powder or a granulate, and preferably further comprising a lubricant.
  • the pharmaceutical composition is in form of a tablet.
  • a subsequent film coating of the tablet may be performed.
  • the tablet may be produced by tabletting, e.g. direct compressing, the phosphate adsorbent as a pure powder, i.e. without containing excipient.
  • the tablet is prepared by compression of the pure powder, i.e. a powder of the phosphate adsorbent without excipient, together with suitable excipients, such as excipients selected from filler, binder, disintegrant, flow agent, lubricant, and mixture thereof.
  • suitable excipients such as excipients selected from filler, binder, disintegrant, flow agent, lubricant, and mixture thereof.
  • the tablet is obtained by compression of the granulated powders (i.e. the "inner phase") together with further excipients (the “outer phase”).
  • the inner phase of the pharmaceutical composition according to the invention may comprise the phosphate adsorbent, and at least one excipient selected from a filler, a binder, a disintegrant, and mixture thereof.
  • the outer phase of the pharmaceutical composition according to the invention may comprise at least one excipient selected from a flow agent, a lubricant, a filler, a disintegrant and mixture thereof.
  • the outer phase comprises a flow agent, a lubricant, and optionally a filler and/or disintegrant.
  • compositions according to the present invention may comprise a filler to provide processability.
  • Suitable filler materials are well-known to the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990), Mack Publishing Co., Easton, PA, pp. 1635-1636 ), and include microcrystalline cellulose, lactose and other carbohydrates, starch, pregelatinized starch, e.g., starch 1500R (Colorcon Corp.), corn starch, dicalcium phosphate, potassium bicarbonate, sodium bicarbonate, cellulose, calcium phosphate dibasic anhydrous, sugars, sodium chloride, and mixtures thereof, of which lactose, micro-crystalline cellulose, pregelatinized starch, and mixtures thereof, are preferred.
  • microcrystalline cellulose (Avicel grades, FMC Corp.), and mixtures comprising microcrystalline cellulose and one or more additional fillers, e.g., corn starch or pregelatinized starch, are particularly useful.
  • the filler is microcrystalline cellulose.
  • the filler may be present in an amount of about 10 to 40 wt.%, based on the total weight of the pharmaceutical composition, preferably 20 to 40 wt%, more preferably about 30 wt%.
  • composition of the invention may contain also the following classes of excipients:
  • a tablet containing the iron(III)-based phosphate adsorbent, and a lubricant, and optionally at least one further excipient selected from a filler, a binder, a disintegrant, and a flow agent, as hereinabove described.
  • the tablet may further comprise at least one excipient selected from an anti-adherent, a glidant, a sweetener, an opacifying or coloring medium, and a flavoring medium, as hereinabove described.
  • the tablet may be coated, e.g. may comprise a film coating.
  • suitable film formers in film coating compositions to be applied to pharmaceutical compositions of the invention comprise e.g. polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydrophilic polymers such as cationic polymers containing dimethylamino-ethyl methacrylate as functional groups (e.g. Eudragit E and EPO), hydroxypropylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose or the like, of which hydroxypropylmethylcellulose is preferred.
  • the film coating composition ingredients include plasticizers, e.g. polyethylene glycols (e.g. polyethylene glycol 6000), triethylcitrate, diethyl phthalate, propylene glycol, glycerin in conventional amounts, as well as the above- mentioned opacifiers such as titanium dioxide, and colorants, e.g. iron oxide, aluminum lakes, etc.
  • plasticizers e.g. polyethylene glycols (e.g. polyethylene glycol 6000), triethylcitrate, diethyl phthalate, propylene glycol, glycerin in conventional amounts, as well as the above- mentioned opacifiers such as titanium dioxide, and colorants, e.g. iron oxide, aluminum lakes, etc.
  • opacifiers e.g. titanium dioxide
  • colorants e.g. iron oxide, aluminum lakes, etc.
  • dry mixtures as Sepifilm or Opadry mixtures, latter prepared by Colorcon Corp.
  • These products may be individually prepared dry
  • the film coating may be generally applied to achieve a weight increase of the tablet of about 1 to 10 wt.%, and preferably about 2 to 6 wt.%, based on the total weight of the pharmaceutical composition.
  • the film coating can be applied by conventional techniques in a suitable coating pan or fluidized bed apparatus using water and/or conventional organic solvents (e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol), ketones (acetone), etc.
  • water and/or conventional organic solvents e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol
  • ketones acetone
  • the iron(III)-based phosphate adsorbent is formulated as an uniquely coated tablet.
  • the tablet according to the invention may be made by direct compression of the iron(III)-based phosphate (the drug substance) and by addition of high concentrations of Mg-stearate (e.g. about 3 to about 5%).
  • the tablet may further comprise binders as e.g. HPMC 3cPs, HP-Cellulose LH-22.
  • Electrostatic dry powder deposition process may increase the structural integrity of the tablet without adding major amounts of material and also provides the opportunity for an unique appearance of the dosage form.
  • the tablet may be coated by a electrostatic dry powder deposition process, e.g. as follows: The coating mixture is prepared by melt-extrusion of a mixture of polymer (preferably Eudragits, e.g. type E, RS.
  • a further step of micronization of the produced melt-extrudate is optionally performed, e.g. with about 7 to 10 micron.
  • the coating process may consist of i) fixing the core (e.g. by vacuum) on a wheel, charged, transported through the coating chamber and attaching the opposite charged coating powder to the core surface, ii) transporting the powder layered core on the wheel to an IR lamp were the coat melts, iii) transferring the core to the adjacent second wheel and repeating the process for the bottom part of the tablet core.
  • Typical coat weights are 3-4% of the core weight and are about 20-50 ⁇ m thick.
  • Heat fixation step The fusion cycle varies from product to product but typically is around 80s per side. This includes heating up the tablets from room temperature, so the temperature at the surface of the tablet peaks at approximately 100°C and in the tablet core approximately 70°C for about 20s.
  • the iron(III)-based phosphate adsorbent according to the invention may also be formulated as semi solid formulations.
  • Such compositions are comfortable to swallow, in particular for elderly and children, and may be considered as a daily supplement rather than a medicine.
  • semi-solid dosage forms have the advantage that they may be filled into multiple or single dose containers.
  • the composition of the invention is in form of an aqueous gel formulation.
  • an aqueous gel may contain a viscosity enhancer which preferably has wetting properties, or a thickener.
  • the viscosity may be selected from polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, and glycerol.
  • the thickener may be selected from starch (e.g. corn starch, potato starch), the starch being preferably heated up, cellulose derivative (e.g. hydroxypropylmethyl cellulose), alginate salt (e.g. sodium alginate), carbomer, colloidal silicon dioxide, and other paste former (such as e.g.
  • preservatives may be added, such as e.g. p-hydroxybenzoic acid methyl ester and salt thereof, p-hydroxyl benzoic acid propylester and salt thereof, sorbic acid and salt thereof, benzoic acid and salt thereof or chlorhexidine.
  • Flavours and sweeteners may also be added.
  • the aqueous gel may contain a buffering system, e.g. citrate or acetate buffer, to ensure the antimicrobial efficacy of the preservative system.
  • the aqueous gel may further contain at least one agent selected from a sweetener, such as e.g. saccharin sodium, aspartame, sucralose and a flavour, such e.g. as strawberry or passion.
  • a sweetener such as e.g. saccharin sodium, aspartame, sucralose and a flavour, such e.g. as strawberry or passion.
  • the aqueous gel may be prepared by solubilizing all excipients, with the exception of the thickener in water purified, dispersing the phosphate adsorbant until vigorous mixing and then by adding the thickener.
  • Possible semi solid formulations include, but are not limited to, swallowable gel, e.g. aqueous or non aqueous gel (the phosphate adsorbent being optionally encapsulated or granulated); chewy bar, e.g. a cereal bar; fast-dispersing dosage, such as orally dispersing wafer; cream ball chewable dosage form; chewable dosage forms, such as candy, soft capsule, or nugget; or edible sachet.
  • the iron(III)-based phosphate adsorbent may contain dietary fiber as insoluble carbohydrate, e.g. the starch may be replaced by dietary fibers.
  • Semi solid formulations have the advantage that they may be perceived as a daily supplement rather than a medicine, which means that a rather large dosage form may be acceptable for the patients. Preferably, these formulations are given to elderly and pediatric patients.
  • Swallowable gel has the advantage of be comfortable to swallow and be possibly perceived as a daily supplement rather than a medicine. In addition there is a wide choice of flavor options. Non-aqueous gels are preferred. Encapsulation of the iron hydroxide and/or a granulation step is preferably included, in order to overcome problems with mouth feeling, e.g. grittyness.
  • the chewy bar may contain ingredients selected from the groups consisting of malt extract, skimmed milk powder, fat reduced cacao, glucose syrup, egg, hardened palm oil (e.g. about 30 weight %, based on the total weight of the bar), yeast, sodium chloride (e.g. about 0.1 weight %, based on the total weight of the bar), vitamin (e.g. vitamin E), favor (e.g. vanilla flavor), one or more stabilizers (e.g. E339, E435, E472b, E475, soy bean lecithin), thickener (e.g. carob flour, E460).
  • the bar may be covered by a milk chocolate layer, e.g.
  • the manufacturing process may comprise blending of all the ingredients in a mixer at elevated temperature and filling the blend into a mold.
  • the bars may be packaged after cooling to room temperature and removal from the mold.
  • Chewing of a chewy bar e.g. a cereal bar is a convenient and patient friendly administration and may be perceived as part of the daily routine, i.e. daily supplement rather than a medicine.
  • Such a dosage form has only minor limitations with respect to the size.
  • Orally dispersing wafers are versatile fast-dispersing dosage form.
  • Orally dispersing wafers containing the phosphate adsorbent of the invention, e.g. iron(III)-based phosphate are particularly suited for pediatric and geriatric populations, since they are comfortable to swallow and may be perceived as a daily supplement rather than a medicine.
  • a rapidly dispersing dosage form may release its active ingredient, i.e. the iron(III)-based phosphate adsorbent, within a period of less than about ninety seconds.
  • active ingredient i.e. the iron(III)-based phosphate adsorbent
  • These dosage forms may exhibit a three-dimensional shape, which can be retained for adequate storage but may be readily dispersed in the presence of excess moisture.
  • the rapidly dispersing dosage e.g. the orally dispersing wafer
  • the rapidly dispersing dosage may be manufactured by a solid, free-form fabrication technique in which objects are built in a laminated fashion through sequential addition of patterned thin layers, e.g. three dimensional printing (3DP).
  • 3DP three dimensional printing
  • the semi-solid dosage may be a cream ball chewable dosage form.
  • the phosphate adsorbent is suspended in a cream or gel and then layered on a core.
  • Various flavors may be used.
  • Such a form may provide better chewability and mouth feeling than other chewable dosage forms.
  • This formulation may be comfortable to swallow and may be perceived as a daily supplement rather than a medicine.
  • chewable dosage forms include for example candy, soft capsule, and nugget.
  • a wide choice of flavor may be used.
  • Fancy shapes and colors can be designed.
  • the chewable dosage form may be packed in a tablet dispenser or individually wrapped.
  • the chewable dosage form may contain ingredients selected from the group consisting of: corn syrup, sugar, partially hydrogenated soybean and cottonseed oil, nonfat milk powder, soy lecithin, natural or artificial flavor, citric acid, glyceryl monostearate, Carrageenan, Red 40, Vitamin (e.g. Vitamin D3 or K1), tricalcium phosphate, alpha tocopheryl, salt, niacinamide, calclium pantothenate, pyridoxine hydrochloride, riboflavin, and thiamine mononitrate.
  • ingredients selected from the group consisting of: corn syrup, sugar, partially hydrogenated soybean and cottonseed oil, nonfat milk powder, soy lecithin, natural or artificial flavor, citric acid, glyceryl monostearate, Carrageenan, Red 40, Vitamin (e.g. Vitamin D3 or K1), tricalcium phosphate, alpha tocopheryl, salt, niacinamide, calclium pantothenate, pyr
  • the ingredients may be dissolved in water or in milk to form a syrup, which may be boiled until it reaches the desired concentration or the sugar starts to caramelize.
  • the liquid may then be filled onto molds and cooled down to harden the dosage form.
  • the phosphate adsorbent may be formulated as an edible sachet. Eating a sachet is a convenient and patient friendly administration and may be perceived as part of the daily routine, i.e. as a daily supplement rather than a medicine.
  • the filing of the edible sachet may be made e.g. consist of, of granules, which may be made of the material as hereinabove described for the chewy bars.
  • the filing of the edible sachet may be made by milling of the bars after removal from the mold.
  • the sachet material may be made of water soluble polysaccharide, e.g. starch, mashed vegetable or fruits, optionally with lipids.
  • the sachet may be manufactured by spraying the fruit or vegetable puree on a fast rotating teflonized disk where it forms a thin film which is dried in a next step.
  • the non soluble carbohydrate contained in the iron(III)-based phosphate adsorbent is a dietary fiber, e.g. Benefiber ® .
  • a dietary fiber e.g. Benefiber ®
  • starch is replaced by dietary fiber, e.g. Benefiber ® .
  • Such a formulation combines the benefits of phosphate binding and of dietary fibers in one product.
  • the iron(III)-based phosphate adsorbent according to the invention exhibit valuable pharmacological properties, e.g. adsorbing inorganic phosphate or phosphate bound to foodstuffs from body fluids or foodstuffs, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
  • the iron(III)-based phosphate adsorbents according to the invention are, therefore, useful in the treatment and/or prevention of hyperphosphataemia, hypercalcaemia, hyperparathyroidism reduction, in cardiovascular morbidity and mortality, renal osteodystrophy, calciphylaxis and soft tissue calcifications.
  • the iron(III)-based he phosphate adsorbents according to the invention are suitable for the treatment and/or prevention of hyperphosphataemia, in humans and warm-blooded animals, in particular companion animals such as dogs and in particular cat
  • the phosphate adsorbents of the invention, and pharmaceutical compositions containing them are more particularly useful in patients with hyperphosphataemia, e.g. for dialysis-dependent patients, e.g. hemodialysis, or patients suffering from advanced chronic kidney diseases (CKD), chronic renal failure, chronic renal insufficiency, end-stage renal disease.
  • CKD advanced chronic kidney diseases
  • the phosphate adsorbent according to the invention may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules.
  • the phosphate adsorbent may be administered through nasogastric tubes, e.g. pediatric naso-gastric tubes.
  • compositions comprising the compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
  • Unit dosage forms for oral administration contain, for example, from about 0.5g to about 7g, e.g. from about 0.5 to about 5 g, e.g. from about 1.0 to about 3 g, preferably from about 1 to about 1.5, more preferably about 1 to about 1.5 g, even more preferably about 1 to about 1.25 g of phosphate adsorbent.
  • the phosphate adsorbent according to the invention may also be used for the absorption of phosphate bound to foodstuffs. They may be admixed with foodstuffs.
  • Patients remain on their current sevelamer treatment during a 2-week run-in period, then enter a 1- to 2-week wash out period prior to being switched to the iron(III)-based phosphate adsorbent as described in Example 1 for 4 weeks: 3.75 g/day, 7.5 g/day, 11.25 g/day, 15 g/day, 22.5 g/day.
  • Each cohort enrolls 10 patients. Patients are stratified by pre-study sevelamer dose: Strata 1 is less than 7.2 g/day of sevelamer in cohorts of 3.75 g/day and 7.5 g/day of the iron(III)-based phosphate adsorbent. Strata 2 is greater or equal to 7.2 g/day of sevelamer in other cohorts of the iron(III)-based phosphate adsorbent treatment.
  • the phosphate adsorbent may be administered as the sole active ingredient or together with another phosphate reducing agent, such as sevelamer; Fosrenol; Ca acetate; or Ca carbonate. It may also be administered in combination with a calcimimetic such as cinacalcet; vitamin D; or calcitriol.
  • another phosphate reducing agent such as sevelamer; Fosrenol; Ca acetate; or Ca carbonate. It may also be administered in combination with a calcimimetic such as cinacalcet; vitamin D; or calcitriol.
  • a phosphate adsorbent according to the invention is administered in conjunction with another phosphate reducing agent, such as sevelamer, Fosrenol, Ca acetate or Ca carbonate; a calcimimetic such as cinacalcet; or with vitamin D or calcitriol, e.g. for preventing or treating hyperphosphataemia or other diseases or disorders as hereinabove specified
  • dosages of the co-administered compound will of course vary depending on the type of co-drug employed, on the condition being treated and so forth.
  • 172kg of the final product are isolated as a reddish brown powder, obtained by spray drying using a NIRO SD42 with appropriate spray drying parameters or with an atomization pressure of 1.2 bar, an outlet temperature of 65°C and an Inlet temperature of 140°C.
  • the product may be filled without any other processing directly into sachets or stick packs.
  • solution A An aqueous solution of 21.1 g sodium carbonate dissolved in 105g water (solution A) and an aqueous solution of 26.5g iron(III) chloride hexahydrate dissolved in 55g water (solution B) are prepared.
  • Solution A (4.2g/min) and B (2.7g/min) are dosed to a suspension of 7.36g potato starch in 40g water over a time span of 30 minutes by continuous mixing of solution A and B and subsequent addition to the potato starch suspension.
  • the resulting brown-reddish suspension is stirred for at least one hour at 25°C, filtered and washed three times with 173.6g water each.
  • To the resulting reddish brown solids 14.6g water 7.36g sucrose and 24.2g ethanol are added and the mixture is stirred for 60 minutes. 18.4g of the final product are obtained by fluidized spray drying using appropriate FSD conditions.
  • Example 3 phosphate binding capacity of the material described in Example 1 or Example 2 determined by ion chromatography/conductivity detection.
  • Reagents Highly pure water (e.g. from Milli-Q-System (Millipore)); Sodium hydroxide (50% (m/m) solution, carbonate free, e.g. Merck 1.58793); 0.1 N Hydrochloric acid (HCl); Hydrochloric acid 37%; Sodium hydrogen phosphate (Na2HPO4).
  • Ion chromatograph with gradient pump Ion chromatograph with gradient pump; Anion exchange column (e.g. Dionex IonPac AS11-HC Length 250 mm, internal diameter 4 mm; or equivalent); Self regenerating anion suppressor (e.g. Dionex ASRS-ULTRA II 4 mm, anion suppressor system), PVDF Filter (e.g. Infochroma: 8817E-PV-4 ECO HPLC-Filter PVDF 0.45 ⁇ m). Chromatographic conditions
  • the system suitability test proves that chloride and phosphate are sufficiently separated. Moreover the repeatability of injection is shown by repetitive injection of the comparison solution for calculation. A blank chromatogram shows that no interfering peak exist in the solvent. A 1/100 dilution of the comparison solution for calculation is used to show sensitivity of the system.
  • Test solution Accurately weigh (to within 0.01 mg) 365.0 to 385.0 mg of the test substance into a 25 mL volumetric flask. Add 20.0 mL of CS1 to this substance and let stand for 10 min . (prepare in duplicate TSx.1 and TSx.2) duplicateTSx.1 Adjust the pH of this suspension to pH 2.0 with HCl 0.1 N and fill to the mark with water. The tightly closed flask is then kept in a water bath of 37°C for 2 hours. Approximately, every half an hour the suspension is stirred manually by shaking the vial. Afterwards, filter approximately 2.0 mL of the resulting suspension through a 0.45 ⁇ m filter (PVDF) into a vial.
  • PVDF 0.45 ⁇ m filter
  • Comparison stock solution Concentration (PO4 3- ) level for CS1 4273 ⁇ g/mL (prepare single: CS1)
  • the analyte peaks in the chromatograms of the test solution is identified by comparing the retention times with those of the peaks in the chromatograms of the comparison solutions.
  • the peak areas for each analyte peak is determined in the chromatograms of the test solutions.
  • the peak areas for each analyte peak is also determined in the chromatograms of the CS2 solutions.
  • the compound of example 1 adsorbs 14.2%m/m phosphate.
  • the compound of example 2 adsorbs 20% m/m phosphate.
  • Example 5 Capsules (direct fill with lubricant).
  • 90% of the product as prepared in example 1 is filled into a mixer.
  • a pre-mix of 7-8% of the same product and 2-3% Mg-stearate is prepared.
  • the premix is screened through a screen (1000 micron mesh size) into the mixer with the rest of the product to prepare the final blend.
  • the final blend is then filled into hard gelatin capsules.
  • Example 6 capsules (direct fill with lubricant and additional excipient).
  • 80 % of the product as prepared in example 1 is mixed together with MCC (10%) or preferably corn starch (10 %).
  • a pre-mix of 7-8% of the same product and 2-3% Mg-stearate is prepared.
  • the premix is screened through a screen (1000 micron mesh size) into the mixer with the rest of the product to prepare the final blend.
  • the final blend is then filled into hard gelatin capsules.
  • Example 7 sachet, stick pack or capsule (granulation by dry compaction)
  • Example 8 sachet, stick pack or capsule (wet granulation)
  • the product as prepared in example 1 is granulated with about 15 % water, related to the dry powder in a high shear mixer. Then the granulate is dried until a LOD (loss on drying) of approx. 6-7 % is reached. Then the dried granulate is screened through a screen, mesh size 2 mm. Finally the screened granulate is filled into stick packs. Optionally, the granulate may also be filled together with a lubricant into capsules .
  • Example 9 sachet, stick pack or capsule (by wet granulation with additional binder)
  • Example 10 Tablet (direct compression with lubricant)
  • Example 11 Tablet (direct compression with lubricant and additional excipients)
  • Example 12 Tablet (granulation by dry compaction)
  • disintegrant is additionally contained in the granulate.
  • an external phase comprising a filler, disintegrant, glidant and lubricant is added to the screened granulate and the final blend is then compressed to tablets which may subsequently be coated.
  • Example 13 Tablet (by wet granulation with additional binder and other excipients)
  • 50% of the product as prepared in example 1 is granulated together with approx. 20% microcrystalline cellulose and approx. 5 % crospovidone, with approximatively 18 % water, related to the dry powder, in a high shear mixer. Then the granulate is dried until a LOD (loss on drying) of about 6-7 % is reached. Then the dried granulate is screened through a screen, mesh size approx. 1.25 mm into a mixer together with 10 % microcrystalline cellulose and approx.5 % crospovidone. A pre-mix of approx. 7% of this mix and about 2% Mg-stearate is prepared.
  • the premix is screened through a screen (1000 micron mesh size) into the mixer with the rest of the product to prepare the final blend.
  • the final blend is then compressed on a tabletting machine to ovaloid tablets of 1100 mg weight (corresponds to 625 mg of product).
  • the tablets are coated with an aqueous suspension of HPMC 3 cps, titanium dioxide, talk and plasticizer(s) or of the corresponding Opadry mixture.
  • Example 14 Tablet (wet granulation with additional binder)
  • Ex21 Ex22 Phosphate adsorbent of example 2 400 400 Lactose monohydrate 472 472 Microcrystalline cellulose 140 140 Starch 70 / Arabinogalactan / 70

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Claims (19)

  1. Adsorbant de phosphate à base de fer (III) comprenant i) un matériau de base adsorbant qui est de l'amidon ii) des hydroxydes polynucléaires d'oxyde de fer (III), et iii) du saccharose, dans lequel ledit saccharose est partiellement incorporé dans les hydroxydes polynucléaires d'oxyde de fer (III), et comprenant en outre un carbonate, caractérisé par une capacité de liaison du phosphate d'au moins environ 140 mg de phosphate adsorbé pour 1 g d'adsorbant phosphate, et caractérisé en ce que ledit adsorbant de phosphate à base de fer (III) est isolé par un séchage par atomisation en lit fluidisé.
  2. Adsorbant de phosphate à base de fer (III) selon l'une quelconque des revendications 1, pour une utilisation en tant que produit pharmaceutique.
  3. Composition utilisable en tant que préparation pharmaceutique pour l'élimination sélective de phosphate inorganique de liquides, où la composition est insoluble dans l'eau et contient un adsorbant de phosphate à base de fer (III) tel que défini dans les revendications 1 ou 2.
  4. Composition pharmaceutique comprenant un adsorbant de phosphate à base de fer (III) selon l'une quelconque des revendications 1 et 2 et comprenant en outre au moins un excipient choisi parmi un conservateur et un liant.
  5. Composition selon la revendication 4, dans laquelle le conservateur est un alcool, de préférence de l'éthanol.
  6. Composition selon la revendication 4 ou 5, où la composition ne contient pas de liant.
  7. Composition selon l'une quelconque des revendications 4 à 6, sous la forme d'une poudre ou d'un produit granulé.
  8. Composition selon la revendication 4 à 7, qui est sous la forme d'un comprimé et comprend en outre un lubrifiant, et éventuellement au moins un autre excipient choisi parmi une charge, un liant, un agent délitant, et un agent d'écoulement.
  9. Procédé pour la préparation d'un adsorbant de phosphate à base de fer (III) contenant de l'hydroxyde d'oxyde de fer (III), de l'amidon et du saccharose, lequel procédé comprend les étapes consistant à :
    (i) faire réagir une solution aqueuse de sel de fer (III) avec une base aqueuse à un pH compris entre 6 et 10, dans lequel la réaction est effectuée en présence d'amidon, en formant un précipité ;
    (ii) isoler le précipité formé selon l'étape i) ;
    (iii) mettre en suspension le précipité provenant de l'étape ii) dans une solution aqueuse ; et
    (iv) ajouter du saccharose pour donner un adsorbant de phosphate à base de fer (III), et éventuellement au moins un excipient choisi parmi un conservateur et un liant
    (v) isoler le produit par séchage par atomisation en lit fluidisé pour donner l'adsorbant de phosphate à base de fer (III) en tant que poudre sèche.
  10. Procédé selon la revendication 9, dans lequel au moins un lavage est effectué entre les étapes ii) et iii) .
  11. Procédé selon l'une quelconque des revendications 9 ou 10, dans lequel, dans l'étape i), le pH de la solution est maintenu à une valeur constante entre 6 et 8, de préférence, environ 7.
  12. Procédé selon l'une quelconque des revendications 9 à 11, où le procédé comprend en outre l'étape vi) de granulation du produit, éventuellement en présence d'au moins un excipient choisi parmi un liant et un lubrifiant, pour donner un adsorbant de phosphate à base de fer (III) en tant que matière granulaire.
  13. Procédé selon l'une quelconque des revendications 9 à 12, où le procédé comprend en outre l'étape vii) de compression en tablette ou du produit obtenu dans l'étape v) ou de la matière granulaire obtenue dans l'étape vi), l'étape de compression en tablette étant éventuellement exécutée en présence d'un excipient choisi parmi une charge, un liant, un agent délitant, un agent d'écoulement, un lubrifiant et un mélange de ceux-ci.
  14. Adsorbant de phosphate à base de fer (III) pouvant être obtenu avec un procédé selon l'une quelconque des revendications 9 à 13.
  15. Forme pharmaceutique solide ou semi-solide contenant l'adsorbant de phosphate à base de fer (III) selon la revendication 1 ou selon la revendication 14.
  16. Forme pharmaceutique solide selon la revendication 15, qui est une poudre, une matière granulaire ou un comprimé, dans laquelle la poudre et la matière granulaire sont éventuellement remplies dans un sachet, un sachet-dose ou une gélule.
  17. Forme pharmaceutique semi-solide selon la revendication 15, qui est un gel aqueux, un gel non aqueux, un gel à avaler, une barre à mâcher, une forme pharmaceutique à dispersion rapide, une forme pharmaceutique à mâcher en boule de crème, une forme pharmaceutique à mâcher ou un sachet comestible.
  18. Adsorbant de phosphate à base de fer (III) selon la revendication 1 ou selon la revendication 14, destiné à être utilisé pour le traitement ou la prévention de l'hyperphosphatémie, l'hypercalcémie, la réduction d'hyperparathyroïdie, la morbidité ou mortalité cardiovasculaire, l'ostéodystrophie rénale, la calciphylaxie et des calcifications des tissus mous, des maladies et des troubles s'y rapportant.
  19. Adsorbant de phosphate à base de fer (III) selon la revendication 1 ou selon la revendication 14, destiné à être utilisé pour le contrôle des taux de produits de phosphate sérique et de calcium-phosphate sérique, tout en maintenant des taux normaux de calcium sérique, chez un sujet nécessitant un tel traitement.
EP11152584.6A 2006-12-14 2007-12-05 Adsorbant de phosphate à base d'iron(III)-glucides Active EP2319804B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
SI200731582T SI2319804T1 (sl) 2006-12-14 2007-12-05 Fosfatni adsorbent na osnovi Ĺľelezo(III)-ogljikovega hidrata
EP11152584.6A EP2319804B1 (fr) 2006-12-14 2007-12-05 Adsorbant de phosphate à base d'iron(III)-glucides
PL11152584T PL2319804T3 (pl) 2006-12-14 2007-12-05 Węglowodanowy adsorbent fosforanów oparty na żelazie (III)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP06126122A EP1932807A1 (fr) 2006-12-14 2006-12-14 Composés inorganiques
EP06126101 2006-12-14
EP11152584.6A EP2319804B1 (fr) 2006-12-14 2007-12-05 Adsorbant de phosphate à base d'iron(III)-glucides
EP07122432A EP1932808A1 (fr) 2006-12-14 2007-12-05 Adsorbant de phosphate à base d'iron(III)-glucides

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP07122432A Division EP1932808A1 (fr) 2006-12-14 2007-12-05 Adsorbant de phosphate à base d'iron(III)-glucides
EP07122432.3 Division 2007-12-05

Publications (2)

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EP2319804A1 EP2319804A1 (fr) 2011-05-11
EP2319804B1 true EP2319804B1 (fr) 2014-10-22

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EP11152584.6A Active EP2319804B1 (fr) 2006-12-14 2007-12-05 Adsorbant de phosphate à base d'iron(III)-glucides
EP07122432A Withdrawn EP1932808A1 (fr) 2006-12-14 2007-12-05 Adsorbant de phosphate à base d'iron(III)-glucides
EP15161751.1A Withdrawn EP2918548A1 (fr) 2006-12-14 2007-12-05 ABSORBANT DE PHOSPHATE BASÉ SUR Fer( III )-CARBOHYDRATE

Family Applications After (2)

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EP07122432A Withdrawn EP1932808A1 (fr) 2006-12-14 2007-12-05 Adsorbant de phosphate à base d'iron(III)-glucides
EP15161751.1A Withdrawn EP2918548A1 (fr) 2006-12-14 2007-12-05 ABSORBANT DE PHOSPHATE BASÉ SUR Fer( III )-CARBOHYDRATE

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EP (3) EP2319804B1 (fr)
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PL (1) PL2319804T3 (fr)

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GB9720061D0 (en) 1997-09-19 1997-11-19 Crosfield Joseph & Sons Metal compounds as phosphate binders
MY157620A (en) 2006-01-31 2016-06-30 Cytochroma Dev Inc A granular material of a solid water-soluble mixed metal compound capable of binding phosphate
GB0714670D0 (en) 2007-07-27 2007-09-05 Ineos Healthcare Ltd Use
GB0720220D0 (en) 2007-10-16 2007-11-28 Ineos Healthcare Ltd Compound
TWI468167B (zh) 2007-11-16 2015-01-11 威佛（國際）股份有限公司 藥學組成物
US20110086097A1 (en) * 2008-06-13 2011-04-14 Daniel Kaufmann Manufacture process for the preparation of an iron containing phosphate adsorbent
EP2334292B1 (fr) * 2008-10-17 2019-05-08 Fresenius Medical Care Holdings, Inc. Procédé de détermination d'un dosage de liant du phosphore pour un patient dialysé
SG173887A1 (en) * 2009-03-02 2011-10-28 Vifor Int Ag Phosphate adsorbent
GB0913525D0 (en) 2009-08-03 2009-09-16 Ineos Healthcare Ltd Method
GB201001779D0 (en) 2010-02-04 2010-03-24 Ineos Healthcare Ltd Composition
WO2013134273A1 (fr) * 2012-03-05 2013-09-12 Luitpold Pharmaceuticals, Inc. Procédés pour la modulation de phosphore et de fgf23
WO2015032941A1 (fr) * 2013-09-09 2015-03-12 Kemira Oyj Procédé pour purifier l'eau
WO2015181205A1 (fr) 2014-05-28 2015-12-03 Biaqua B.V. Procédé pour l'élimination de phosphate dans des fractions d'eau
GB2527902A (en) * 2014-05-30 2016-01-06 Johnson Matthey Plc Method for preparing a sorbent
WO2016038541A1 (fr) * 2014-09-10 2016-03-17 Lupin Limited Procédé de fabrication d'un adsorbant contenant du fer
EP3932535A1 (fr) 2020-07-01 2022-01-05 Vifor Fresenius Medical Care Renal Pharma, Ltd. Procédé de fabrication de composés de fer polynucléaires stabilisés par des glucides et/ou de l'acide humique

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US4970079A (en) 1989-06-05 1990-11-13 Purdue Research Foundation Method and composition of oxy-iron compounds for treatment of hyperphosphatemia
DE4239442C2 (de) * 1992-11-24 2001-09-13 Sebo Gmbh Verwendung eines mit polynuklearen Metalloxidhydroxiden modifizierten Adsorptionsmaterials zur selektiven Elimination von anorganischem Phosphat aus proteinhaltigen Flüssigkeiten
DE19547356A1 (de) * 1995-12-19 1997-06-26 Vifor Int Ag Adsorbens für Phosphat aus wäßrigem Medium, dessen Herstellung und Verwendung
JPWO2003053565A1 (ja) * 2001-12-21 2005-04-28 室町ケミカル株式会社 リン酸の吸着剤
US6903235B2 (en) 2003-10-08 2005-06-07 Panion & Bf Biotech Inc. Pharmaceutical-grade ferric citrate
DE102004031181A1 (de) * 2004-06-28 2006-01-19 Vifor (International) Ag Phosphatadsorbens
MY157620A (en) 2006-01-31 2016-06-30 Cytochroma Dev Inc A granular material of a solid water-soluble mixed metal compound capable of binding phosphate

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Publication number Publication date
PL2319804T3 (pl) 2015-03-31
EP1932808A1 (fr) 2008-06-18
DK2319804T3 (en) 2015-01-19
EP2319804A1 (fr) 2011-05-11
EP2918548A1 (fr) 2015-09-16

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